Characterization of the MPS I-H knock-in mouse reveals increased femoral biomechanical integrity with compromised material strength and altered bone geometry

Abstract

Mucopolysaccharidosis type I (MPS I), is an autosomal recessive lysosomal storage disorder caused by a deficiency in the α-L-iduronidase enzyme, resulting in decreased enzymatic activity and accumulation of glycosaminoglycans. The disorder phenotypically manifests with increased urine glycosaminoglycan excretion, facial dysmorphology, neuropathology, cardiac manifestations, and bone deformities. While the development of new treatment strategies have shown promise in attenuating many symptoms associated with the disorder, the bone phenotype remains unresponsive. The aim of this study was to investigate and further characterize the skeletal manifestations of the Idua-W392X knock-in mouse model, which carries a nonsense mutation corresponding to the IDUA-W402X mutation found in Hurler syndrome (MPS I-H) patients. μCT analysis of the microarchitecture demonstrated increased cortical thickness, trabecular number, and trabecular connectivity along with decreased trabecular separation in the tibiae of female homozygous Idua-W392X knock-in (IDUA−/−) mice, and increased cortical thickness in male IDUA−/− tibiae. Cortical density, as determined by μCT, and bone mineral density distribution, as determined by quantitative backscattered microscopy, were equivalent in IDUA−/− and wildtype (Wt) bone. However, tibial porosity was increased in IDUA−/− cortical bone. Raman spectroscopy results indicated that tibiae from female IDUA−/− had decreased phosphate to matrix ratios and increased carbonate to phosphate ratios compared to Wt female tibiae, whereas these ratios remained equivalent in male IDUA−/− and Wt tibiae. Femora demonstrated altered geometry and upon torsional loading to failure analysis, female IDUA−/− mouse femora exhibited increased torsional ultimate strength, with a decrease in material strength relative to Wt littermates. Taken together, these findings suggest that the IDUA−/− mutation results in increased bone torsional strength by altering the overall bone geometry and the microarchitecture which may be a compensatory response to increased porosity, reduced bone tensile strength and altered physiochemical composition.

Liver-directed gene therapy corrects neurologic disease in a murine model of mucopolysaccharidosis type I-Hurler

“…The abnormal femoral length in the early stage may be due to abnormalities in the growth plate caused by GAG accumulation in MPS I mice. 27 The osteoclast activity of the femur in this MPS I model was 4-fold higher than in wild-type femora. 28 Our study showed that there was no significant difference in femur length between 5-month-old MPS I mice and wild-type mice, suggesting that the abnormal femur length of this MPS I mouse model might return to normal at 5 months of age.…”

A selective ER ‐phagy exerts procollagen quality control via a Calnexin‐ FAM 134B complex

“…We sought to determine whether PC molecules accumulate in the lysosomes of LSD osteoblasts. Saos2 osteoblasts in which the alpha‐L‐iduronidase gene was deleted using CRISPR‐Cas9 technology (CRISPR‐IDUA) represent a disease model of mucopolysaccharidosis type I (MPS I), a lysosomal storage disorder with severe skeletal manifestations (Oestreich et al , ). Similar to cells treated with BafA1, CRISPR‐IDUA showed swollen lysosomes, suggesting an accumulation of undigested substrates in the lysosomal lumen (Fig I).…”

Differences in MPS I and MPS II Disease Manifestations

“…Canine animal models for MPS I tend to show milder manifestations compared to humans afflicted by the disease [170][171][172]. The introduction of exact mutations in mouse models provides insights into the genetics of the disease [173,174]. However, the small size and short lifespan of mice need to be considered when evaluating therapeutic efficiency.…”